Learning to pair therapies and the expanding matrix for pulmonary arterial hypertension: is more better?

Study design for treatment of a rare disease with few therapeutic options is straightforward as “something is likely better than nothing”. With the surge of therapeutic options for pulmonary arterial hypertension (PAH) since the late 1990s, trials have been designed based on limited data without the luxury of patient numbers. As community physicians can offer combination therapy without evidence of benefit, clinical trialists are challenged to accrue patients to studies to prove what some envision is intuitively obvious, that combining active agents is likely to be better than treatment with a single agent. PAH is a debilitating, progressive condition with diverse causes, and for a disease with no therapeutic cure, targeting multiple pathways concurrently is appealing. However, without prior evidence for safety and activity, it is entirely possible that some combinations might be more harmful than helpful. PAH is an angioproliferative vasculopathy resulting from abnormal endothelial and smooth muscle cell interactions, which leads to a progressive narrowing of the pulmonary arteries and their branches, resulting in right-heart failure and death. At the cellular level, PAH is characterised by vasoconstriction, endothelial dysfunction and smooth muscle cell proliferation of the pulmonary arterioles, a process known as vascular remodelling, and in situ thrombosis of the small pulmonary arteries 1, 2. Proliferating endothelial cells obliterate medium-sized pre-capillary arteries 3, 4, thereby forming the characteristic “plexiform” lesions. At the molecular level, the balance of vasculature regulation shifts towards factors that produce vasoconstriction and smooth muscle cell proliferation. Animal models and culture of cells from patients with PAH have demonstrated dysregulation of specific mediators of various signalling pathways, including: prostacyclin 5–7; nitric oxide (NO); and endothelin 8–10. Angiopoietins 11, 12, autoantibodies 13, and proinflammatory cytokines and chemokines have also been implicated 14. …